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Cardiogenic shock in the setting of severe aortic stenosis is associated with poor outcomes. We describe 5 patients with cardiogenic shock and severe aortic stenosis who received an axillary microaxial pump (Impella) as an extended bridge to transcatheter aortic valve replacement. The median (range) age was 65 (61-87) years old, 80% were male, and 80% presented with stage D or E cardiogenic shock. In most cases, balloon aortic valvuloplasty was performed prior to pump insertion. Stabilization by Impella allowed for heart team evaluation and additional interventions, including percutaneous coronary intervention, MitraClip, and cardioversion. After a median (range) of 7 (5-14) days of Impella support, semi-elective transcatheter aortic valve replacement was successfully performed. All patients survived to discharge. Four patients (80%) were alive beyond 1 year. In these high-risk patients, prolonged support with a microaxial pump allowed for stabilization, ancillary interventions, and multi-disciplinary heart team evaluation prior to transcatheter aortic valve replacement.

Accurate estimation of low-density lipoprotein cholesterol (LDL-C) is important for guiding cholesterol-lowering therapy. Different methods currently exist to estimate LDL-C.This study sought to assess discordance of estimated LDL-C using the Friedewald, Sampson, and Martin/Hopkins equations.Electronic health record data from patients with atherosclerotic cardiovascular disease and triglyceride (TG) levels of 400 mg/dL between October 1, 2015, and June 30, 2019, were retrospectively analyzed. LDL-C was estimated using the Friedewald, Sampson, and Martin/Hopkins equations. Patients were categorized as concordant if LDL-C was 70 mg/dL with each pairwise comparison of equations and as discordant if LDL-C was 70 mg/dL for the index equation and ≥70 mg/dL for the comparator.The study included 146,106 patients with atherosclerotic cardiovascular disease (mean age: 68 years; 56% male; 91% White). The Martin/Hopkins equation consistently estimated higher LDL-C values than the Friedewald and Sampson equations. Discordance rates were 15% for the Friedewald vs Martin/Hopkins comparison, 9% for the Friedewald vs Sampson comparison, and 7% for the Sampson vs Martin/Hopkins comparison. Discordance increased at lower LDL-C cutpoints and in those with elevated TG levels. Among patients with TG levels of ≥150 mg/dL, a10 mg/dL difference in LDL-C was present in 67%, 27%, and 23% of patients when comparing the Friedewald vs Martin/Hopkins, Friedewald vs Sampson, and Sampson vs Martin/Hopkins equations, respectively.Clinically meaningful differences in estimated LDL-C exist among equations, particularly at TG levels of ≥150 mg/dL and/or lower LDL-C levels. Reliance on the Friedewald and Sampson equations may result in the underestimation and undertreatment of LDL-C in those at increased risk.

With continued growth of transcatheter aortic valve replacement (TAVR), safe alternative access remains important for patients without adequate transfemoral (TF) access. Registry-based outcomes with transcarotid (TC) TAVR are favorable compared to transapical or transaxillary/subclavian, but TC vs TF comparisons have not been made. Our objective was to compare outcomes between TF and TC access routes for TAVR at a high-volume United States center. Methods: We retrospectively evaluated all TF and TC TAVR procedures from June 11, 2014 (first TC case) through December 31, 2019. The primary outcomes were 30-day stroke and 30-day mortality. Secondary outcomes were 1-year stroke, 1-year survival, and 30-day and 1-year life-threatening/major bleeding, vascular complications, and myocardial infarction. Propensity score weighted (PSW) models were used to compare risk-adjusted TF and TC outcomes. Of 1,465 TAVR procedures, 1319 (90%) were TF and 146 (10%) were TC. Procedure time and length of stay did not differ between groups. Unadjusted 30-day stroke (TF = 2.0%, TC = 2.7%, P = 0.536) and mortality (TF = 2.1%, TC = 2.7%, P = 0.629) were similar between groups. PSW 30-day stroke (odds ratio (OR) (95% confidence interval (CI)) = 0.8 (0.2-2.8)) and mortality (OR (95% CI) = 0.8 (0.2-3.0)) were similar between groups. Unadjusted and PSW 30-day major/life threatening bleeding, major vascular complications, and myocardial infarction did not differ between groups. Survival at one year was 90% (88%-92%) for TF patients and 87% (81%-93%) for TC patients (unadjusted P = 0.28, PSW hazard ratio = 1.0 (0.6-1.7)). Transcarotid TAVR is associated with similar outcomes compared to transfemoral TAVR at an experienced, high-volume center.

Background Nine oral disease-modifying therapies (DMTs) have been approved for the treatment of multiple sclerosis (MS) in the United States. Few studies have examined self-reported quality of life (QoL) and functional status outcomes among patients who switch to oral medications from injectable MS therapies. This study compares self-reported QoL and disability status between participants switching from injectable to oral DMTs, to those who stay on injectable DMTs continuously for the same time period. Methods Longitudinal data were assessed from relapsing MS participants in the Pacific Northwest MS Registry completing a minimum of two surveys between 2012 and 2018 with a maximum of 36 months between surveys. Stayers were defined as those who remained on injectable DMTs continuously from Time 1 to Time 2; switchers were those who switched from injectable to either fingolimod, teriflunomide or dimethyl fumarate during the same time interval. Outcomes of interest were physical and psychological QoL, measured by the Multiple Sclerosis Impact Scale (MSIS-29), and disability, measured by the Patient Determined Disease Steps (PDDS). To analyze the effect of switching to oral DMT on outcomes at Time 2, a one-to-two propensity score matching (PSM) was used to match switchers to stayers. Outcomes at Time 2 were analyzed using paired t-test for QoL scores, and Stuart Maxwell test for PDDS as a categorical variable. Results Among 2385 participants who returned consecutive yearly surveys, 413 met the inclusion criteria for stayers and 66 for switchers. After one-to-two PSM, 124 stayers were matched to 62 switchers. Paired t-test showed no differences between switchers and stayers for physical (mean difference: − 0.41; [95% confidence interval CI: − 3.3-2.4]; p = 0.78) or psychological (mean difference: − 0.23; [95% CI, − 1.6- 1.1]; p = 0.74) QoL. Additionally, no differences were seen between switchers and stayers in self-reported disability status. Conclusions MS registry participants who switched to an oral DMT from injectable showed no significant differences in QoL or self-reported disability status compared to those remaining on injectable DMT continuously in the same time period.

Multiple class I and class IIa recommendations exist related to surgical ablation (SA) of atrial fibrillation (AF) in patients undergoing cardiac surgery.Examine temporal trends and predictors of SA for AF in a large US healthcare system.We retrospectively analyzed data from the Society for Thoracic Surgery (STS) Adult Cardiac Surgery Database for 21 hospitals in the Providence St. Joseph Health system. All patients with preoperative AF who underwent isolated coronary artery bypass graft (CABG) surgery, isolated aortic valve replacement (AVR), AVR with CABG surgery (AVR+CABG), isolated mitral valve repair or replacement (MVRr), and MVRr with CABG surgery (MVRr+CABG) from July 1, 2014, to March 31, 2020 were included. Temporal trends in SA were evaluated using the Cochran-Armitage trends test. A multilevel logistic regression model was used to examine patient-, hospital-, and surgeon-level predictors of SA.Among 3124 patients with preoperative AF, 910 (29.1%) underwent SA. This was performed most often in those undergoing isolated MVRr (n = 324, 44.8%) or MVRr+CABG (n = 75, 35.2%). Rates of SA increased over time and were highly variable between hospitals. Years since graduation from medical school for the primary operator was one of the few predictors of SA: odds ratio (95% confidence interval) = 0.71 (0.56-0.90) for every 10-year increase. Annual surgical (both hospital and operator) and AF catheter ablation volumes were not predictive of SA.Wide variability in rates of SA for AF exist, underscoring the need for greater preoperative collaboration between cardiologists, electrophysiologists, and cardiac surgeons.

Background The COVID-19 pandemic has disrupted routine cardiovascular care, with unclear impact on procedural deferrals and associated outcomes across diverse patient populations. Methods Cardiovascular procedures performed at 30 hospitals across six Western states in two large, non-profit healthcare systems (Providence St. Joseph Health and Stanford Healthcare) from December 2018-June 2020 were analyzed for changes over time. Risk-adjusted in-hospital mortality was compared across pandemic phases with multivariate logistic regression. Results Among 36,125 procedures (69% percutaneous coronary intervention, 13% coronary artery bypass graft surgery, 10% transcatheter aortic valve replacement, and 8% surgical aortic valve replacement), weekly volumes changed in two distinct phases after the initial inflection point on February 23, 2020: an initial period of significant deferral (COVID I: March 15 to April 11) followed by recovery (COVID II: April 12 onwards). Compared to pre-COVID, COVID I patients were less likely to be female (p=0.0003), older (p, Graphical Abstract Image, graphical abstract

Importance Hospitals are reimbursed based on Diagnosis Related Groups (DRGs), which are defined, in part, by patients having 1 or more complications or comorbidities within a given DRG family. Hospitals have made substantial investment in efforts to document these complications and comorbidities. Objective To examine temporal trends in DRGs with a major complication or comorbidity, compare these findings with 2 alternative measures of disease severity, and estimate associated changes in payment. Design, Setting, and Participants This retrospective cohort study used data from the all-payer National Inpatient Sample for admissions assigned to 1 of the top 20 reimbursed DRG families at US acute care hospitals from January 1, 2012, to December 31, 2016. Data were analyzed from July 10, 2018, to May 29, 2019. Exposures Quarter year of hospitalization. Main Outcomes and Measures The primary outcome was the proportion of DRGs with a major complication or comorbidity. Secondary outcomes were comorbidity scores, risk-adjusted mortality rates, and estimated payment. Changes in assigned DRGs, comorbidity scores, and risk-adjusted mortality rates were analyzed by linear regression. Payment changes were estimated for each DRG by calculating the Centers for Medicare & Medicaid Services weighted payment using 2012 and 2016 case mix and hospitalization counts. Results Between 2012 and 2016, there were 62 167 976 hospitalizations for the 20 highest-reimbursed DRG families; the sample was 32.9% male and 66.8% White, with a median age of 57 years (interquartile range, 31-73 years). Within 15 of these DRG families (75%), the proportion of DRGs with a major complication or comorbidity increased significantly over time. Over the same period, comorbidity scores were largely stable, with a decrease in 6 DRG families (30%), no change in 10 (50%), and an increase in 4 (20%). Among 19 DRG families with a calculable mortality rate, the risk-adjusted mortality rate significantly decreased in 8 (42%), did not change in 9 (47%), and increased in 2 (11%). The observed DRG shifts were associated with at least $1.2 billion in increased payment. Conclusions and Relevance In this cohort study, between 2012 and 2016, the proportion of admissions assigned to a DRG with major complication or comorbidity increased for 15 of the top 20 reimbursed DRG families. This change was not accompanied by commensurate increases in disease severity but was associated with increased payment.

Background: Procedural anticoagulation with bivalirudin (BIV), trans-radial intervention (TRI), and use of a vascular closure device (VCD) are thought to mitigate percutaneous coronary intervention (PCI)-related bleeding. We compared the impact of these bleeding avoidance strategies (BAS) for PCIs stratified by bleeding risk. Methods: We performed a retrospective cohort analysis of PCIs from 18 facilities within one health care system from 2009Q3 to 2017Q4. Bleeding risk was assessed per the National Cardiovascular Data Registry CathPCI bleeding model, with procedures stratified into 6 categories (first, second, third quartiles, 75th–90th, 90th–97.5th, and top 2.5th percentiles). Regression models were used to assess the impact of BAS on bleeding outcome. Results: Of 74 953 PCIs, 9.4% used no BAS, 12.0% used BIV alone, 20.8% used TRI alone, 26.8% used VCD alone, 5.4% used TRI+BIV, and 25.6% used VCD+BIV. The crude bleeding rate was 4.4% overall. Only 2 comparisons showed significant trends across all risk strata: VCD+BIV versus no BAS, odds ratio (95% CI) range: first quartile, 0.36 (0.18–0.72) to top 2.5th percentile, 0.50 (0.32–0.78); TRI versus no BAS, odds ratio (95% CI) range: first quartile, 0.15 (0.06–0.38) to top 2.5th percentile, 0.49 (0.28–0.86). TRI had lower odds of bleeding compared with BIV for all risk strata except the top 2.5th percentile. Addition of BIV to TRI did not change the odds of bleeding for any risk strata. Factors potentially limiting use of TRI (renal failure, shock, cardiac arrest, and mechanical circulatory support) were present in ≤10% of procedures below the 90th percentile. Conclusions: Among individual BAS, only TRI had consistently lower odds of bleeding across all risk strata. Factors potentially limiting TRI were found infrequently in procedures below the 90th percentile of bleeding risk. For transfemoral PCI, VCD+BIV had lower odds of bleeding compared with no BAS across all risk strata.

BACKGROUND Intrathoracic complications (ITC) requiring emergency surgical intervention occur during transcatheter aortic valve replacement (TAVR). OBJECTIVES Characterize the incidence, outcomes and predictors of ITC in a large cohort of transfemoral (TF) TAVR cases over a 5 year period. METHODS Retrospective registry and chart review of all nonclinical trial TF-TAVR patients from seven centers within one hospital system from 2012-2016. ITC were defined as cardiac perforation, new or worsening pericardial effusion/tamponade, annular rupture, thoracic aortic injury, aortic valve dislodgement, and coronary artery occlusion. Procedural and 30-day outcomes and 1-year mortality were compared between ITC and no ITC patients. Multivariable logistic regression was used to identify predictors of ITC. RESULTS Over the study period, 1,581 patients had TF-TAVR and 68 ITC occurred in 46 patients (2.9%). The most common ITCs were pericardial effusion/tamponade (59%), cardiac perforation (33%), and valve dislodgement (33%). ITC rate did not decline over time (rate (95% confidence interval) for 2012 = 0% (0-8.8%), 2013 = 1.3% (0-7.2%), 2014 = 4.4% (2.2-8.0%), 2015 = 3.5% (2.0-5.6%), and 2016 = 2.4% (1.5-3.8%)). ITC patients had worse 1-year survival (ITC: 60.7% (45.1-73.1%), no ITC: 88.7% (87.0-90.3%); p

Highlights • More than half of adults with ASCVD meet the definition of very high risk status. • Risk assessment has received appreciably less attention in secondary prevention. • ML techniques offer a simplified means to identify higher risk ASCVD patients., Objective The 2018 American Heart Association/American College of Cardiology (AHA/ACC) Blood Cholesterol Guideline recommendation to classify patients with atherosclerotic cardiovascular disease (ASCVD) as very high-risk (VHR) vs not-VHR (NVHR) has important implications for escalation of medical therapy. We aimed to define the prevalence and clinical characteristics of these two groups within a large multi-state healthcare system and develop a simpler means to assist clinicians in identifying VHR patients using classification and regression tree (CART) analysis. Methods We performed a retrospective analysis of all patients in a 28-hospital US healthcare system in 2018. ICD-10 codes were used to define the ASCVD population. Per the AHA/ACC Guideline, VHR status was defined by ≥2 major ASCVD events or 1 major ASCVD event and ≥2 high-risk conditions. CART analysis was performed on training and validation datasets. A random forest model was used to verify results. Results Of 180,669 ASCVD patients identified, 58% were VHR. Among patients with a history of myocardial infarction (MI) or recent acute coronary syndrome (ACS), 99% and 96% were classified as VHR, respectively. Both CART and random forest models identified recent ACS, ischemic stroke, hypertension, peripheral artery disease, history of MI, and age as the most important predictors of VHR status. Using five rules identified by CART analysis, fewer than 50% of risk factors were required to assign VHR status. Conclusion CART analysis helped to streamline the identification of VHR patients based on a limited number of rules and risk factors. This approach may help improve clinical decision making by simplifying ASCVD risk assessment at the point of care. Further validation is needed, however, in more diverse populations., Graphical abstract Image, graphical abstract

PURPOSE: HER2 copy number by fluorescence in situ hybridization (FISH) is typically reported relative to the centromere enumeration probe 17 (CEP17). HER2/CEP17 ratio could be impacted by alterations in the number of chromosome 17 copies. Monosomy of chromosome 17 (m17) is found in ~1,900 cases of early stage HER2-positive breast cancer annually in the United States, however the efficacy of HER2-directed trastuzumab therapy in these patients is not well characterized. Here we retrospectively identified HER2-amplified, stage I-III breast cancers with m17 and characterized the impact of trastuzumab treatment. METHODS: From January 1, 2000 to June 1, 2011 we identified 99 women with HER2-amplified m17 breast cancers, as defined by a CEP17 signal of

Tip links are thought to gate the mechanically sensitive transduction channels of hair cells, but how they form during development and regeneration remains mysterious. In particular, it is unclear how tip links are strung between stereocilia so that they are oriented parallel to a single axis; why their polarity is uniform despite their constituent molecules' intrinsic asymmetry; and why only a single tip link is present at each tip-link position. We present here a series of simple rules that reasonably explain why these phenomena occur. In particular, our model relies on each of the two ends of the tip link having distinct Ca 2+ -dependent stability and being connected to different motor complexes. A simulation employing these rules allowed us to explore the parameter space for the model, demonstrating the importance of the feedback between transduction channels and angled links, links that are 60° off-axis with respect to mature tip links. We tested this key aspect of the model by examining angled links in chick cochlea hair cells. As implied by the assumptions used to generate the model, we found that angled links were stabilized if there was no tip link at the tip of the upper stereocilium, and appeared when transduction channels were blocked. The model thus plausibly explains how tip-link formation and pruning can occur.

Background: Rapid evaluation of dysphagia poststroke significantly lowers rates of aspiration pneumonia. Logistical barriers often significantly delay in-person dysphagia evaluation by speech language pathologists (SLPs) in remote and rural hospitals. Clinical swallow evaluations delivered via telehealth have been validated in a number of clinical contexts, yet no one has specifically validated a teleswallow evaluation for in-hospital post-stroke dysphagia assessment. Methods: A team of 6 SLPs experienced in stroke care and a telestroke neurologist designed, implemented, and tested a teleswallow evaluation for acute stroke patients, in which 100 patients across 2 affiliated, urban certified stroke centers were sequentially evaluated by a bedside and telehealth SLP. Inter-rater reliability was analyzed using percent agreement, Cohen's kappa, Kendall's tau-b, and Wilcoxon matched-pairs signed rank tests. Logistic regression models accounting for age and gender were used to test the impact of stroke severity and stroke location on agreement. Results: We found excellent agreement for both liquid (91% agreement; kappa = 0.808; Kendall's tau-b = 0.813, p < 0.001; Wilcoxon signed rank = -0.818, p = 0.417) and solid (87% agreement; kappa = 0.792; Kendall's tau-b = 0.844, p < 0.001; Wilcoxon signed rank = 0.243, p = 0.808) dietary textures. From regression modeling, there is suggestive but inconclusive evidence that higher National Institute of Health Stroke Scale (NIHSS) scores correlate with lower levels of agreement for liquid diet recommendations (OR [95% CI] 0.895 [0.793-1.01]; p = 0.07). There was no impact of NIHSS score for solid diet recommendations and no impact of stroke location on solid or liquid diet recommendations. Qualitatively, we identified professional, logistical, technical, and patient barriers to implementation, many of which resolved with experience over time. Conclusions: Dysphagia evaluation by a remote SLP via telehealth is safe and effective following stroke. We plan to implement teleswallow across our multistate telestroke network as standard practice for poststroke dysphagia evaluation.

Background: A wireless pulmonary artery pressure sensor (CardioMEMS) is approved for implantation via the femoral vein. The internal jugular vein (IJ) is an attractive alternative access route commonly used in pulmonary artery catheterization. Methods and Results: Retrospective chart review was performed for all sensor implants from 10 providers at 4 centers from September 2016 to June 2018. To compare procedural outcomes and discharge efficiency between groups, multivariate analyses incorporating potential confounders were performed. Seventy-three (28%) patients had femoral access, and 189 (72%) had IJ access; demographics were similar between the groups. Complications, including one case of hematoma and 4 cases of mild hemoptysis, and 30-day mortality (2%–3%) did not differ between groups. Provider preference for IJ access substantially increased over time, with IJ accounting for 90% of cases in 2018. After risk-adjustment, IJ cases had 20% (5%–33%) shorter fluoroscopy time ( P =0.01) and 24% (7%–38%) lower contrast volume ( P =0.008). Compared with outpatient femoral cases, outpatient IJ cases had 62% (52%–69%) faster needle-to-door time and were 34 times (6–235) more likely to have same-day discharge ( P Conclusions: IJ access for CardioMEMS implant is a safe alternative associated with superior procedural and discharge outcomes. Implanters at 4 high-volume centers adopted IJ access as the preferred implant approach.

Objective Vascular complications (VC) and bleeding complications impact morbidity and mortality after transfemoral transcatheter aortic valve replacement (TF-TAVR). Few contemporary studies have detailed these complications, associated treatment strategies, or clinical outcomes. We examined the incidence, predictors, treatment strategies, and outcomes of VCs in a multicenter cohort of patients undergoing TF-TAVR. Methods We performed a retrospective registry and chart review of all nonclinical trial TF-TAVR patients from seven centers within a five-state hospital system from 2012 to 2016. Bleeding and VC were recorded as defined by the Valve Academic Research Consortium recommendations. Procedural and 30-day outcomes and 1-year mortality were compared between patients with no, minor, or major VC. Multivariable logistic and Cox regressions were used to identify predictors of major VC and mortality, respectively. Results Over the study period, 1573 patients underwent TF-TAVR, with 96 (6.1%) experiencing a major VC and 77 (4.9%) experiencing a minor VC. The majority of VCs were access site related (74.2%), occurred intraoperatively (52.6%), and required interventional treatment (73.2%). The site, timing, and treatment method of VCs did not significantly change over the study period. Patients with VCs had a greater need for blood transfusion, longer postoperative length of stay, higher rates of cardiac events, increased vascular-related 30-day readmission, and higher 30-day mortality. Female sex (odds ratio [OR], 3.00; 95% CI, 1.91-4.72) and prior percutaneous coronary intervention (OR, 2.14 ; 95% CI, 1.38-3.31) were the strongest predictors of major VC. VCs modestly decreased over the study period: every 90-day increase in surgery date decreased the odds of major VC by 6% (95% CI, 1%-10%). Patients with major VCs had worse 1-year survival (OR, 79%; 95% CI, 69%-86%) compared with patients with minor VCs (OR, 92%; 95% CI, 82%-96%) or no VCs (OR, 88%; 95% CI, 87%-90%; P = .002). However, for patients who survived more than 30 days, the 1-year survival did not differ between groups For patients who survived more than 30 days, male sex (hazard ratio, 1.84; 95% CI, 1.30-2.60) and the logit of STS mortality risk score (hazard ratio, 1.98; 95% CI, 1.48-2.65) were the strongest predictors of mortality. After adjusting for other factors, minor and major VC were not predictors of 1-year mortality for patients who survived more than 30 days. Conclusions In our contemporary cohort, VCs after TF-TAVR have modestly decreased in recent years, but continue to impact perioperative outcomes. Patient selection, consideration of alternative access routes, and prompt recognition and treatment of VCs are critical elements in optimizing early clinical outcomes after TF-TAVR.

Background Heart failure (HF) management guided by CardioMEMS™ pulmonary artery pressure (PAP) monitoring reduces PAP and HF hospitalizations. The objective of this project was to characterize the relationship between medication adjustments, PAP change, and outcomes for all patients at an advanced HF center. Methods We retrospectively analyzed medication changes and hospitalizations for 32 consecutive patients implanted with the CardioMEMS™ sensor at a single HF center and related these outcomes to PAP data from the Merlin.net (Abbott) database. Absolute change in PAP from baseline was estimated using area under the curve normalized to days monitored. Results Patients had an average change in mean PAP of -3.9±1.3 mmHg at 6 months and -5.7±2.1 mmHg at 12 months. Compared to the pre-implant time period, hospital days for HF-related hospitalizations decreased by 6.9 (95% CI = 3.3-10.5) days per patient at 6 months (p35mmHg experienced a drop in PAP while their number of medication adjustments decreased, and patients with baseline PAP

Supplemental material, Supplemental Material1 for Reducing return of disease activity in patients with relapsing multiple sclerosis transitioned from natalizumab to teriflunomide: 12-month interim results of teriflunomide therapy by Stanley L Cohan, Keith Edwards, Lindsay Lucas, Tiffany Gervasi-Follmar, Judy O’Connor, Jessica Siuta, Vineetha Kamath, Lore Garten, Chiayi Chen, James Thomas, Kyle Smoot, Kiren Kresa-Reahl and Kateri J Spinelli in Multiple Sclerosis Journal–Experimental, Translational and Clinical

Background Natalizumab is an effective treatment for relapsing multiple sclerosis. Return of disease activity upon natalizumab discontinuance creates the need for follow-up therapeutic strategies. Objective To assess the efficacy of teriflunomide following natalizumab discontinuance in relapsing multiple sclerosis patients. Methods Clinically stable relapsing multiple sclerosis patients completing 12 or more consecutive months of natalizumab, testing positive for anti-John Cunningham virus antibody, started teriflunomide 14 mg/day, 28 ± 7 days after their final natalizumab infusion. Physical examination, Expanded Disability Status Scale, laboratory assessments, and brain magnetic resonance imaging were performed at screening and multiple follow-up visits. Results Fifty-five patients were enrolled in the study. The proportion of patients relapse-free was 0.94, restricted mean time to first gadolinium-enhancing lesion was 10.9 months and time to 3-month sustained disability worsening was 11.8 months. The mean number of new or enlarging T2 lesions per patient at 12 months was 0.42. Exploratory analyses revealed an annualized relapse rate of 0.08, and a proportion of patients with no evidence of disease activity of 0.68. Forty-seven patients (85.5%) reported adverse events, 95% of which were mild to moderate. Conclusions Teriflunomide therapy initiated without natalizumab washout resulted in a low rate of return of disease activity. Clinicians may consider this a worthwhile strategy when transitioning clinically stable patients off natalizumab to another therapy. ClinicalTrials.gov Identifier: NCT01970410

Phosphorylation of alpha-synuclein at serine-129 is an important marker of pathologically relevant, aggregated forms of the protein in several important human diseases, including Parkinson's disease, Dementia with Lewy bodies, and Multiple system atrophy. Although several kinases have been shown to be capable of phosphorylating alpha-synuclein in various model systems, the identity of the kinase that phosphorylates alpha-synuclein in the Lewy body remains unknown. One member of the Polo-like kinase family, PLK2, is a strong candidate for being the Lewy body kinase. To examine this possibility, we have used a combination of approaches, including biochemical, immunohistochemical, and in vivo multiphoton imaging techniques to study the consequences of PLK2 genetic deletion on alpha-synuclein phosphorylation in both the presynaptic terminal and preformed fibril-induced Lewy body pathology in mouse cortex. We find that PLK2 deletion reduces presynaptic terminal alpha-synuclein serine-129 phosphorylation, but has no effect on Lewy body phosphorylation levels. Serine-129 mutation to the phosphomimetic alanine or the unphosphorylatable analog aspartate does not change the rate of cell death of Lewy inclusion-bearing neurons in our in vivo multiphoton imaging paradigm, but PLK2 deletion does slow the rate of neuronal death. Our data indicate that inhibition of PLK2 represents a promising avenue for developing new therapeutics, but that the mechanism of neuroprotection by PLK2 inhibition is not likely due to reducing alpha-synuclein serine-129 phosphorylation and that the true Lewy body kinase still awaits discovery.

Importance The coronavirus disease 2019 (COVID-19) pandemic has changed health care delivery worldwide. Although decreases in hospitalization for acute myocardial infarction (AMI) have been reported during the pandemic, the implication for in-hospital outcomes is not well understood. Objective To define changes in AMI case rates, patient demographics, cardiovascular comorbidities, treatment approaches, and in-hospital outcomes during the pandemic. Design, Setting, and Participants This cross-sectional study retrospectively analyzed AMI hospitalizations that occurred between December 30, 2018, and May 16, 2020, in 1 of the 49 hospitals in the Providence St Joseph Health system located in 6 states (Alaska, Washington, Montana, Oregon, California, and Texas). The cohort included patients aged 18 years or older who had a principal discharge diagnosis of AMI (ST-segment elevation myocardial infarction [STEMI] or non–ST-segment elevation myocardial infarction [NSTEMI]). Segmented regression analysis was performed to assess changes in weekly case volumes. Cases were grouped into 1 of 3 periods: before COVID-19 (December 30, 2018, to February 22, 2020), early COVID-19 (February 23, 2020, to March 28, 2020), and later COVID-19 (March 29, 2020, to May 16, 2020). In-hospital mortality was risk-adjusted using an observed to expected (O/E) ratio and covariate-adjusted multivariable model. Exposure Date of hospitalization. Main Outcomes and Measures The primary outcome was the weekly rate of AMI (STEMI or NSTEMI) hospitalizations. The secondary outcomes were patient characteristics, treatment approaches, and in-hospital outcomes of this patient population. Results The cohort included 15 244 AMI hospitalizations (of which 4955 were for STEMI [33%] and 10 289 for NSTEMI [67%]) involving 14 724 patients (mean [SD] age of 68 [13] years and 10 019 men [66%]). Beginning February 23, 2020, AMI-associated hospitalizations decreased at a rate of –19.0 (95% CI, –29.0 to –9.0) cases per week for 5 weeks (early COVID-19 period). Thereafter, AMI-associated hospitalizations increased at a rate of +10.5 (95% CI, +4.6 to +16.5) cases per week (later COVID-19 period). No appreciable differences in patient demographics, cardiovascular comorbidities, and treatment approaches were observed across periods. The O/E mortality ratio for AMI increased during the early period (1.27; 95% CI, 1.07-1.48), which was disproportionately associated with patients with STEMI (1.96; 95% CI, 1.22-2.70). Although the O/E mortality ratio for AMI was not statistically different during the later period (1.23; 95% CI, 0.98-1.47), increases in the O/E mortality ratio were noted for patients with STEMI (2.40; 95% CI, 1.65-3.16) and after risk adjustment (odds ratio, 1.52; 95% CI, 1.02-2.26). Conclusions and Relevance This cross-sectional study found important changes in AMI hospitalization rates and worse outcomes during the early and later COVID-19 periods. Future studies are needed to identify contributors to the increased mortality rate among patients with STEMI.

Background: Following approval of dimethyl fumarate (DMF), we established a registry of relapsing multiple sclerosis (RMS) patients taking DMF at our community MS center. Objective: To track DMF patients’ tolerability, disease progression, and lymphopenia. Methods: Patients prescribed DMF for RMS from March 2013 to March 2016 were prospectively enrolled ( N = 412). Baseline data, clinical relapses, magnetic resonance imaging (MRI) activity, discontinuation, and lymphocyte counts were captured through chart review. Results: The mean age of patients starting DMF was 49.4 ± 12.0 years and 70% transitioned from a previous disease-modifying therapy (DMT). Of the patients, 38% discontinued DMF, 76% of whom discontinued due to side effects. Clinical relapse and MRI activity were low. Comparing patients who transitioned from interferon-β (IFN), glatiramer acetate (GA), or natalizumab (NTZ), patients previously on NTZ had higher rates of relapse than those previously on GA (annualized relapse rate p = 0.039, percent relapse p = 0.021). Grade III lymphopenia developed in 11% of patients. Lymphopenia was associated with older age ( p Conclusion: Given the high rates of lymphopenia and discontinuation, it has become our clinical practice to more closely scrutinize older patients and those with a longer disease duration who are potential candidates for initiating DMF therapy.

Purpose: To evaluate patient characteristics that may lead to inappropriate dietary texture recommendations by Teleswallow evaluation by Speech Language Pathologists (SLPs). Background: Following stroke, screening for dysphagia using a swallow evaluation is essential for patient safety. Liquid and solid diet recommendations are given per our standardized four-level scale, ranging from nothing by mouth (NPO) to regular for solid and thin for liquid. We have previously shown good agreement between tele- and bedside swallow evaluation by SLPs, for both liquid and solid dietary textures. In this study, we sought to determine whether patient characteristics account for slight differences in inter-rater reliability. Methods: Kendall’s tau-b and Wilcoxon Signed Rank test for related samples were used to look for significant differences between teleswallow and bedside swallow recommendations for patients with left and right stroke locations or varying levels of stroke severity measured by NIHSS. Evaluations for robot vs bedside swallow screens were categorized as in “agreement” or “disagreement”. Logistic regressions, with age and gender added as covariates, were then used to test the effects of NIHSS and stroke location on the odds of agreement of teleswallow and bedside swallow recommendations. Results: One hundred stroke patients received both evaluations with median 42.0 minutes between evaluations. The average patient age was 67.7 (±14.4) and 50% were female. Median NIHSS score was 4 (interquartile range (IQR) = 7), and 53% (n = 48) of patients had left-brain strokes and 47% (n = 42) had right-brain strokes. Our analysis showed no significant differences between recommendations for stroke location, for either liquid or solid textures. There was also no significant impact on the odds of agreement based on severity, by NIHSS score, for solid textures. However, the odds of agreement between recommendations for liquid textures were 13% less per NIHSS point (OR = 0.876, 95% CI 0.772 - 0.993, p = 0.04). Conclusion: Stroke severity had a small impact on the agreement between teleswallow and bedside recommendations for liquid, but not solid, diet textures.

Parkinson's disease and dementia with Lewy bodies are associated with abnormal neuronal aggregation of α-synuclein. However, the mechanisms of aggregation and their relationship to disease are poorly understood. We developed anin vivomultiphoton imaging paradigm to study α-synuclein aggregation in mouse cortex with subcellular resolution. We used a green fluorescent protein-tagged human α-synuclein mouse line that has moderate overexpression levels mimicking human disease. Fluorescence recovery after photobleaching (FRAP) of labeled protein demonstrated that somatic α-synuclein existed primarily in an unbound, soluble pool. In contrast, α-synuclein in presynaptic terminals was in at least three different pools: (1) as unbound, soluble protein; (2) bound to presynaptic vesicles; and (3) as microaggregates. Serial imaging of microaggregates over 1 week demonstrated a heterogeneous population with differing α-synuclein exchange rates. The microaggregate species were resistant to proteinase K, phosphorylated at serine-129, oxidized, and associated with a decrease in the presynaptic vesicle protein synapsin and glutamate immunogold labeling. Multiphoton FRAP provided the specific binding constants for α-synuclein's binding to synaptic vesicles and its effective diffusion coefficient in the soma and axon, setting the stage for future studies targeting synuclein modifications and their effects. Ourin vivoresults suggest that, under moderate overexpression conditions, α-synuclein aggregates are selectively found in presynaptic terminals.

Bleeding after percutaneous coronary intervention (PCI) is associated with increased morbidity, mortality, and cost. Transradial access (TRA), bivalirudin (BIV), and vascular closure devices (VCD) are strategies to reduce bleeding. We compared the impact of these bleeding avoidance strategies (BAS)

The incidence of Takotsubo Cardiomyopathy (TC) has risen steadily over the past decade, with current estimates of 15-30 cases per 100,000 per year. Historically, men diagnosed with TC have worse outcomes compared to women. The relationship between total hospital charges, number of procedures

In high-risk patients with severe aortic stenosis, transfemoral (TF) access for transcatheter aortic valve replacement (TAVR) is the preferred access route but is not always feasible. Compared with other alternative access routes, transcarotid (TC) access is often overlooked by many valvular heart teams.We report our single-center experience of all patients undergoing TC (n = 25), transapical (TA) (n = 12), or TF (n = 100; limited to most recent cases) TAVR over a 1.5 year period. In-hospital and 30-day outcomes were retrospectively compared between groups using the Kruskal-Wallis and Wilcoxon rank sum tests.TAVR was successfully performed through the left or right carotid artery in all 25 patients. Procedurally, TC and TF procedures were faster than TA procedures (p 0.001), and patients who underwent TC and TF procedures had shorter intensive care unit (ICU) hours (p = 0.05), ventilator hours (p0.001), and length of stay (LOS) (p = 0.01) compared to patients who underwent a TA procedure. No patients who underwent a TC procedure had in-hospital stroke, transient ischemic attack (TIA), or myocardial infarction (MI). One patient who underwent a TC procedure had a TIA by 30-day follow-up, which was not significantly different from the TF (2 patients) or TA groups (0 patients; p = 0.75). In-hospital mortality rates were the same between TC (1 patient) and TF (1 patient) procedures but were significantly greater for TA procedures (2 patients; p = 0.009). Thirty-day mortality rates were low and did not differ between the groups.In our US community hospital setting, TC-TAVR is a safe alternative to TF-TAVR in appropriate patients and has evolved to be our alternative access route of choice if TF access is not feasible.

The quantitative trait locus ahl8 is a key contributor to the early-onset, age-related hearing loss of DBA/2J mice. A non-synonymous nucleotide substitution in the mouse fascin-2 gene (Fscn2) is responsible for this phenotype, confirmed by wild-type BAC transgene rescue of hearing loss in DBA/2J mice. In chickens and mice, FSCN2 protein is abundant in hair-cell stereocilia, the actin-rich structures comprising the mechanically sensitive hair bundle, and is concentrated towards stereocilia tips of the bundle's longest stereocilia. FSCN2 expression increases when these stereocilia differentially elongate, suggesting that FSCN2 controls filament growth, stiffens exposed stereocilia, or both. Because ahl8 accelerates hearing loss only in the presence of mutant cadherin 23, a component of hair-cell tip links, mechanotransduction and actin crosslinking must be functionally interrelated.

Stroke produces a region of complete cell death and areas of partial damage, injury, and gliosis. The spatial relationship of these regions of damage to the infarct core and within spared neuronal circuits has not been identified. A model of cortical stroke was developed within functional subsets of the somatosensory cortex. Infarct size, regions of apoptosis, oxidative DNA damage, heat shock protein induction, and subtypes of reactive gliosis were precisely mapped with the somatosensory body map, quantified, and interrelated. Three tissue microenvironments were recognized: zones of partial ischemic damage, heat shock protein induction, and distributed gliosis. These three zones involved progressively more distant cortical regions, each larger than the infarct core. The zone of partial ischemic damage represents an overlap region of apoptotic cell death, oxidative DNA damage, loss of synaptic connections, and local reactive gliosis. The zone of distributed gliosis occupies distinct functional areas of the somatosensory cortex. The tissue reorganization induced by stroke is much larger than the stroke site itself. Adjacent tissue microenvironments are sites of distinct reactive cellular signaling and may serve as a link between the processes of acute cell death and delayed neuronal plasticity after focal stroke.

The CardioMEMS pressure sensor (St. Jude Medical, St. Paul, Minnesota) was shown in the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) trial to reduce the risk of hospitalization in patients with symptomatic heart failure

During development of the chick cochlea, actin crosslinkers and barbed-end cappers presumably influence growth and remodeling of the actin paracrystal of hair cell stereocilia. We used mass spectrometry to identify and quantify major actin-associated proteins of the cochlear sensory epithelium from E14 to E21, when stereocilia widen and lengthen. Tight actin crosslinkers (i.e. fascins, plastins, and espin) are expressed dynamically during cochlear epithelium development between E7 and E21, with FSCN2 replacing FSCN1 and plastins remaining low in abundance. Capping protein, a barbed-end actin capper, is located at stereocilia tips; it is abundant during growth phase II, when stereocilia have ceased elongating and are increasing in diameter. Capping protein levels then decline during growth phase III, when stereocilia reinitiate barbed-end elongation. Although actin crosslinkers are readily detected by electron microscopy in developing chick cochlea stereocilia, quantitative mass spectrometry of stereocilia isolated from E21 chick cochlea indicated that tight crosslinkers are present there in stoichiometric ratios relative to actin that are much lower than their ratios for vestibular stereocilia. These results demonstrate the value of quantitation of global protein expression in chick cochlea during stereocilia development.

Sound detection by inner ear hair cells requires tip links that interconnect mechanosensory stereocilia and convey force to yet unidentified transduction channels. Current models postulate a static composition of the tip link, with protocadherin 15 (PCDH15) at the lower and cadherin 23 (CDH23) at the upper end of the link. In terminally differentiated mammalian auditory hair cells, tip links are subjected to sound-induced forces throughout an organism's life. Although hair cells can regenerate disrupted tip links and restore hearing, the molecular details of this process are unknown. We developed a novel implementation of backscatter electron scanning microscopy to visualize simultaneously immuno-gold particles and stereocilia links, both of only a few nanometers in diameter. We show that functional, mechanotransduction-mediating tip links have at least two molecular compositions, containing either PCDH15/CDH23 or PCDH15/PCDH15. During regeneration, shorter tip links containing nearly equal amounts of PCDH15 at both ends appear first. Whole-cell patch-clamp recordings demonstrate that these transient PCDH15/PCDH15 links mediate mechanotransduction currents of normal amplitude but abnormal Ca(2+)-dependent decay (adaptation). The mature PCDH15/CDH23 tip link composition is re-established later, concomitant with complete recovery of adaptation. Thus, our findings provide a molecular mechanism for regeneration and maintenance of mechanosensory function in postmitotic auditory hair cells and could help identify elusive components of the mechanotransduction machinery.

We optimized Fluo-4 AM loading of chicken cochlea to report hair-bundle Ca(2+) signals in populations of hair cells. The bundle Ca(2+) signal reported the physiological state of the bundle and cell; extruding cells had very high bundle Fluo-4 fluorescence, cells with intact bundles and tip links had intermediate fluorescence, and damaged cells with broken tip links had low fluorescence. Moreover, Fluo-4 fluorescence in the bundle correlated with Ca(2+) entry through transduction channels; mechanically activating transduction channels increased the Fluo-4 signal, while breaking tip links with Ca(2+) chelators or blocking Ca(2+) entry through transduction channels each caused bundle and cell-body Fluo-4 fluorescence to decrease. These results show that when tip links break, bundle and soma Ca(2+) decrease, which could serve to stimulate the hair cell's tip-link regeneration process. Measurement of bundle Ca(2+) with Fluo-4 AM is therefore a simple method for assessing mechanotransduction in hair cells and permits an increased understanding of the interplay of tip links, transduction channels, and Ca(2+) signaling in the hair cell.

Hair bundles of the inner ear have a specialized structure and protein composition that underlies their sensitivity to mechanical stimulation. Using mass spectrometry, we identified and quantified >1,100 proteins, present from a few to 400,000 copies per stereocilium, from purified chick bundles; 336 of these were significantly enriched in bundles. Bundle proteins that we detected have been shown to regulate cytoskeleton structure and dynamics, energy metabolism, phospholipid synthesis and cell signaling. Three-dimensional imaging using electron tomography allowed us to count the number of actin-actin cross-linkers and actin-membrane connectors; these values compared well to those obtained from mass spectrometry. Network analysis revealed several hub proteins, including RDX (radixin) and SLC9A3R2 (NHERF2), which interact with many bundle proteins and may perform functions essential for bundle structure and function. The quantitative mass spectrometry of bundle proteins reported here establishes a framework for future characterization of dynamic processes that shape bundle structure and function.

Measuring the abundance of many proteins over a broad dynamic range requires accurate quantitation. We show empirically that, in MS experiments, relative quantitation using summed dissociation-product ion-current intensities is accurate, albeit variable from protein to protein, and outperforms spectral counting. By applying intensities to quantify proteins in two complex but related tissues, chick auditory and vestibular sensory epithelia, we find that glycolytic enzymes are enriched threefold in auditory epithelia, whereas enzymes responsible for oxidative phosphorylation are increased at least fourfold in vestibular epithelia. This striking difference in relative use of the two ATP-production pathways likely reflects the isolation of the auditory epithelium from its blood supply, necessary to prevent heartbeat-induced mechanical disruptions. The global view of protein expression afforded by label-free quantitation with a wide dynamic range reveals molecular specialization at a tissue or cellular level.

The curry spice curcumin plays a protective role in mouse models of neurodegenerative diseases, and can also directly modulate aggregation of α-synuclein protein in vitro, yet no studies have described the interaction of curcumin and α-synuclein in genetic synucleinopathy mouse models. Here we examined the effect of chronic and acute curcumin treatment in the Syn-GFP mouse line, which overexpresses wild-type human α-synuclein protein. We discovered that curcumin diet intervention significantly improved gait impairments and resulted in an increase in phosphorylated forms of α-synuclein at cortical presynaptic terminals. Acute curcumin treatment also caused an increase in phosphorylated α-synuclein in terminals, but had no direct effect on α-synuclein aggregation, as measured by in vivo multiphoton imaging and Proteinase-K digestion. Using LC-MS/MS, we detected ~5 ng/mL and ~12 ng/mL free curcumin in the plasma of chronic or acutely treated mice, with a glucuronidation rate of 94% and 97%, respectively. Despite the low plasma levels and extensive metabolism of curcumin, these results show that dietary curcumin intervention correlates with significant behavioral and molecular changes in a genetic synucleinopathy mouse model that mimics human disease.

A study now demonstrates that the transduction channel responsible for converting sound to neural signals in the mammalian cochlea is excluded from the tallest row of stereocilia and is instead more likely in the bottom row.